Anatomy and Neuroscience - Research Publications
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ItemPurinergic mechanisms in the control of gastrointestinal motility(SPRINGER, 2008-09)For many years, ATP and adenosine have been implicated in movement regulation of the gastrointestinal tract. They act through three major receptor subtypes: adenosine or P1 receptors, P2X receptors and P2Y receptors. Each of these major receptor types can be subdivided into several different classes and is widely distributed amongst various neurons, muscle types, glia and interstitial cells that regulate intestinal functions. Several key roles for the different receptors and their endogenous ligands have been identified in physiological and pharmacological studies. For example, adenosine acting at A(1) receptors appears to inhibit intestinal motility in various pathological conditions. Similarly, ATP acting at P2Y receptors is an important component of inhibitory neuromuscular transmission, acting as a cotransmitter with nitric oxide. ATP acting at P2X and P2Y(1) receptors is important for synaptic transmission in simple descending excitatory and inhibitory reflex pathways. Some P2Y receptor subtypes prefer uridine nucleotides over purine nucleotides. Thus, roles for UTP and UDP as enteric transmitters in place of ATP cannot be excluded. ATP also appears to be important for sensory transduction, especially in chemosensitive pathways that initiate local inhibitory reflexes. Despite this evidence, data are lacking about the roles of either adenosine or ATP in more complex motility patterns such as segmentation or the interdigestive migrating motor complex. Clarification of roles for purinergic transmission in these common, but understudied, motility patterns will depend on the use of subtype-specific antagonists that in some cases have not yet been developed.
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ItemExpression of muscarinic receptor subtypes in tree shrew ocular tissues and their regulation during the development of myopia(MOLECULAR VISION, 2009-03-02)PURPOSE: Muscarinic receptors are known to regulate several important physiologic processes in the eye. Antagonists to these receptors such as atropine and pirenzepine are effective at stopping the excessive ocular growth that results in myopia. However, their site of action is unknown. This study details ocular muscarinic subtype expression within a well documented model of eye growth and investigates their expression during early stages of myopia induction. METHODS: Total RNA was isolated from tree shrew corneal, iris/ciliary body, retinal, choroidal, and scleral tissue samples and was reverse transcribed. Using tree shrew-specific primers to the five muscarinic acetylcholine receptor subtypes (CHRM1-CHRM5), products were amplified using polymerase chain reaction (PCR) and their identity confirmed using automated sequencing. The expression of the receptor proteins (M1-M5) were also explored in the retina, choroid, and sclera using immunohistochemistry. Myopia was induced in the tree shrew for one or five days using monocular deprivation of pattern vision, and the expression of the receptor subtypes was assessed in the retina, choroid, and sclera using real-time PCR. RESULTS: All five muscarinic receptor subtypes were expressed in the iris/ciliary body, retina, choroid, and sclera while gene products corresponding to CHRM1, CHRM3, CHRM4, and CHRM5 were present in the corneal samples. The gene expression data were confirmed by immunohistochemistry with the M1-M5 proteins detected in the retina, choroid, and sclera. After one or five days of myopia development, muscarinic receptor gene expression remained unaltered in the retinal, choroidal, and scleral tissue samples. CONCLUSIONS: This study provides a comprehensive profile of muscarinic receptor gene and protein expression in tree shrew ocular tissues with all receptor subtypes found in tissues implicated in the control of eye growth. Despite the efficacy of muscarinic antagonists at inhibiting myopia development, the genes of the muscarinic receptor subtypes are neither regulated early in myopia (before measurable axial elongation) nor after significant structural change.
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ItemImmunolocalization of serotonin in Onychophora argues against segmental ganglia being an ancestral feature of arthropods.(Springer Science and Business Media LLC, 2007-07-15)BACKGROUND: Onychophora (velvet worms) represent the most basal arthropod group and play a pivotal role in the current discussion on the evolution of nervous systems and segmentation in arthropods. Although there is a wealth of information on the immunolocalization of serotonin (5-hydroxytryptamine, 5-HT) in various euarthropods, as yet no comparable localization data are available for Onychophora. In order to understand how the onychophoran nervous system compares to that of other arthropods, we studied the distribution of serotonin-like immunoreactive neurons and histological characteristics of ventral nerve cords in Metaperipatus blainvillei (Onychophora, Peripatopsidae) and Epiperipatus biolleyi (Onychophora, Peripatidae). RESULTS: We demonstrate that paired leg nerves are the only segmental structures associated with the onychophoran nerve cord. Although the median commissures and peripheral nerves show a repeated pattern, their arrangement is independent from body segments characterized by the position of legs and associated structures. Moreover, the somata of serotonin-like immunoreactive neurons do not show any ordered arrangement in both species studied but are instead scattered throughout the entire length of each nerve cord. We observed neither a serially iterated nor a bilaterally symmetric pattern, which is in contrast to the strictly segmental arrangement of serotonergic neurons in other arthropods. CONCLUSION: Our histological findings and immunolocalization experiments highlight the medullary organization of the onychophoran nerve cord and argue against segmental ganglia of the typical euarthropodan type being an ancestral feature of Onychophora. These results contradict a priori assumptions of segmental ganglia being an ancestral feature of arthropods and, thus, weaken the traditional Articulata hypothesis, which proposes a sistergroup relationship of Annelida and Arthropoda.
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ItemNo Preview AvailableType 1 angiotensin receptor pharmacology: signaling beyond G proteins.(Elsevier BV, 2007-01)Drugs that inhibit the production of angiotensin II (AngII) or its access to the type 1 angiotensin receptor (AT(1)R) are prescribed to alleviate high blood pressure and its cardiovascular complications. Accordingly, much research has focused on the molecular pharmacology of AT(1)R activation and signaling. An emerging theme is that the AT(1)R generates G protein dependent as well as independent signals and that these transduction systems separately contribute to AT(1)R biology in health and disease. Regulatory molecules termed arrestins are central to this process as is the capacity of AT(1)R to crosstalk with other receptor systems, such as the widely studied transactivation of growth factor receptors. AT(1)R function can also be modulated by polymorphisms in the AGTR gene, which may significantly alter receptor expression and function; a capacity of the receptor to dimerize/oligomerize with altered pharmacology; and by the cellular environment in which the receptor resides. Together, these aspects of the AT(1)R "flavour" the response to angiotensin; they may also contribute to disease, determine the efficacy of current drugs and offer a unique opportunity to develop new therapeutics that antagonize only selective facets of AT(1)R function.
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ItemNo Preview AvailableAn Integrated Object Model and Method Framework for Subject-Centric e-Research Applications.(Frontiers Media SA, 2009)A framework that integrates an object model, research methods (workflows), the capture of experimental data sets and the provenance of those data sets for subject-centric research is presented. The design of the Framework object model draws on and extends pre-existing object models in the public domain. In particular the Framework tracks the state and life cycle of a subject during an experimental method, provides for reusable subjects, primary, derived and recursive data sets of arbitrary content types, and defines a user-friendly and practical scheme for citably identifying information in a distributed environment. The Framework is currently used to manage neuroscience Magnetic Resonance and microscopy imaging data sets in both clinical and basic neuroscience research environments. The Framework facilitates multi-disciplinary and collaborative subject-based research, and extends earlier object models used in the research imaging domain. Whilst the Framework has been explicitly validated for neuroimaging research applications, it has broader application to other fields of subject-centric research.
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ItemNo Preview AvailableLocalisation of GPR30, a novel G protein-coupled oestrogen receptor, suggests multiple functions in rodent brain and peripheral tissues(BIOSCIENTIFICA LTD, 2009-08)Recently, the G protein-coupled receptor GPR30 has been identified as a novel oestrogen receptor (ER). The distribution of the receptor has been thus far mapped only in the rat central nervous system. This study was undertaken to map the distribution of GPR30 in the mouse brain and rodent peripheral tissues. Immunohistochemistry using an antibody against GPR30 revealed high levels of GPR30 immunoreactivity (ir) in the forebrain (e.g. cortex, hypothalamus and hippocampus), specific nuclei of the midbrain (e.g. the pontine nuclei and locus coeruleus) and the trigeminal nuclei and cerebellum Purkinje layer of the hindbrain in the adult mouse brain. In the rat and mouse periphery, GPR30-ir was detected in the anterior, intermediate and neural lobe of the pituitary, adrenal medulla, renal pelvis and ovary. In situ hybridisation histochemistry using GPR30 riboprobes, revealed intense hybridisation signal for GPR30 in the paraventricular nucleus and supraoptic nucleus (SON) of the hypothalamus, anterior and intermediate lobe of the pituitary, adrenal medulla, renal pelvis and ovary of both rat and mouse. Double immunofluorescence revealed GPR30 was present in both oxytocin and vasopressin neurones of the paraventricular nucleus and SON of the rat and mouse brain. The distribution of GPR30 is distinct from the other traditional ERs and offers an additional way in which oestrogen may mediate its effects in numerous brain regions and endocrine systems in the rodent.
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ItemNo Preview AvailablemGluR1 receptors contribute to non-purinergic slow excitatory transmission to submucosal VIP neurons of guinea-pig ileum(FRONTIERS MEDIA SA, 2009)Vasoactive intestinal peptide (VIP) immunoreactive secretomotor neurons in the submucous plexus are involved in mediating bacterial toxin-induced hypersecretion leading to diarrhoea. VIP neurons become hyperexcitable after the mucosa is exposed to cholera toxin, which suggests that the manipulation of the excitability of these neurons may be therapeutic. This study used standard intracellular recording methods to systematically characterize slow excitatory postsynaptic potentials (EPSPs) evoked in submucosal VIP neurons by different stimulus regimes (1, 3 and 15 pulse 30 Hz stimulation), together with their associated input resistances and pharmacology. All slow EPSPs were associated with a significant increase in input resistance compared to baseline values. Slow EPSPs evoked by a single stimulus were confirmed to be purinergic, however, slow EPSPs evoked by 15 pulse trains were non-purinergic and those evoked by 3 pulse trains were mixed. NK(1) or NK(3) receptor antagonists did not affect slow EPSPs. The group I mGluR receptor antagonist, PHCCC reduced the amplitude of purinergic and non-purinergic slow EPSPs. Blocking mGluR(1) receptors depressed the overall response to 3 and 15 pulse trains, but this effect was inconsistent, while blockade of mGluR(5) receptors had no effect on the non-purinergic slow EPSPs. Thus, although other receptors are almost certainly involved, our data indicate that there are at least two pharmacologically distinct types of slow EPSPs in the VIP secretomotor neurons: one mediated by P2Y receptors and the other in part by mGluR(1) receptors.
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ItemNo Preview AvailableDevelopment of enteric neuron diversity(WILEY, 2009-07)The mature enteric nervous system (ENS) is composed of many different neuron subtypes and enteric glia, which all arise from the neural crest. How this diversity is generated from neural crest-derived cells is a central question in neurogastroenterology, as defects in these processes are likely to underlie some paediatric motility disorders. Here we review the developmental appearance (the earliest age at which expression of specific markers can be localized) and birthdates (the age at which precursors exit the cell cycle) of different enteric neuron subtypes, and their projections to some targets. We then focus on what is known about the mechanisms underlying the generation of enteric neuron diversity and axon pathfinding. Finally, we review the development of the ENS in humans and the etiologies of a number of paediatric motility disorders.
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ItemNo Preview AvailableThe lymphatic anatomy of the breast and its implications for sentinel lymph node biopsy: A Human Cadaver Study(SPRINGER, 2008-03)BACKGROUND: Current understanding of the lymphatic system of the breast is derived mainly from the work of the anatomist Sappey in the 1850s, with many observations made during the development and introduction of breast lymphatic mapping and sentinel node biopsy contributing to our knowledge. METHODS: Twenty four breasts in 14 fresh human cadavers (5 male, 9 female) were studied. Lymph vessels were identified with hydrogen peroxide and injected with a lead oxide mixture and radiographed. The specimens were cross sectioned and radiographed to provide three dimensional images. Lymph (collecting) vessels were traced from the periphery to the first-tier lymph node. RESULTS: Lymph collecting vessels were found evenly spaced at the periphery of the anterior upper torso draining radially into the axillary lymph nodes. As they reached the breast some passed over and some through the breast parenchyma, as revealed in the cross-section studies. The pathways showed no significant difference between male and female specimens. We found also perforating lymph vessels that coursed beside the branches of the internal mammary vessels, draining into the ipsilateral internal mammary lymphatics. In some studies one sentinel node in the axilla drained almost the entire breast. In most more than one sentinel node was represented. CONCLUSION: These anatomical findings are discordant with our current knowledge based on previous studies and demand closer examination by clinicians. These anatomical studies may help explain the percentage of false-negative sentinel node biopsy studies and suggest the peritumoral injection site for accurate sentinel lymph node detection.
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ItemNo Preview AvailableA method for detecting functional activity related expression in gross brain regions, specific brain nuclei and individual neuronal cell bodies and their projections(BIOMED CENTRAL LTD, 2007-02-20)We have developed a system to visualize functionally activated neurons and their projections in the brain. This system utilizes a transgenic mouse, fos-tau-lacZ (FTL), which expresses the marker gene, lacZ, in neurons and their processes after activation by many different stimuli. This system allows the imaging of activation from the level of the entire brain surface, through to individual neurons and their projections. The use of this system involves detection of neuronal activation by histochemical or immunohistochemical detection of beta-galactosidase (betagal), the product of the lacZ gene. Furthermore, the underlying brain state of the FTL mice determines the basal levels of expression of betagal. Here we describe in detail our protocols for detection of FTL expression in these mice and discuss the main variables which need to be considered in the use of these mice for the detection and mapping of functionally activated neurons, circuits and regions in the brain.